TPM2

Chr 9AD

tropomyosin 2

Also known as: AMCD1, CMYO23, CMYP23, DA1, DA2B, DA2B4, HEL-S-273, NEM4

NCBI Gene: 7169 ENSG00000198467 UniProt: P07951 OMIM: 190990

Beta-tropomyosin is an actin filament binding protein primarily expressed in slow, type 1 muscle fibers that regulates muscle contraction. Mutations cause autosomal dominant congenital myopathies including cap disease and nemaline myopathy, as well as distal arthrogryposis syndromes types 1A and 2B4. The pathogenic mechanism involves altered expression of other sarcomeric tropomyosin proteins through a dominant-negative effect.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes beta-tropomyosin, a member of the actin filament binding protein family, and mainly expressed in slow, type 1 muscle fibers. Mutations in this gene can alter the expression of other sarcomeric tropomyosin proteins, and cause cap disease, nemaline myopathy and distal arthrogryposis syndromes. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2009]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Arthrogryposis, distal, type 1AMIM #108120

Arthrogryposis, distal, type 2B4MIM #108120

Congenital myopathy 23MIM #609285

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · TPM2-related myopathy · AD · ClinGen 2021

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.83

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.83LOEUF

pLI 0.000

Z-score 2.12

OE 0.47 (0.28–0.83)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

2.13Z-score

OE missense 0.52 (0.43–0.62)

80 obs / 154.7 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.47 (0.28–0.83)

0≤0.351.4

Missense OE?0.52 (0.43–0.62)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 9 / 19.0Missense obs/exp: 80 / 154.7Syn Z: -0.19

Background carrier burden — how many people carry a rare variant somewhere in TPM2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 280

351 rare PASS variants

Rare truncating (LoF)

1 in 970

80 rare PASS variants

Rare synonymous (reference)

1 in 200

217 rare PASS variants

Rare missense and truncating variants are carried at similar rates in TPM2; this gene does not show strong loss-of-function constraint by this measure. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 390	1 in 850
South Asian	~43k	1 in 270	1 in 1,900
Remaining (unassigned)	~30k	1 in 190	1 in 350
European (Finnish)	~27k	1 in 2,000	1 in 700
Admixed American	~22k	1 in 240	1 in 1,300
African / African American	~21k	1 in 230	1 in 720
East Asian	~20k	1 in 320	1 in 2,200
Ashkenazi Jewish	~13k	1 in 570	≈ 1 in 5,900
Middle Eastern	~2,884	1 in 240	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 9 coding exons well covered in gnomAD exomes and genomes.? see exons ↓